TBCK syndrome: a rare multi-organ neurodegenerative disease

Abstract

TBCK syndrome is an autosomal recessive disorder primarily characterized by global developmental delay, hypotonia, abnormal magnetic resonance imaging (MRI), and distinctive craniofacial phenotypes. High variability is observed among affected individuals and their corresponding variants, making clinical diagnosis challenging. Here, we discuss recent breakthroughs in clinical considerations, TBCK function, and therapeutic development.

Keywords: bone abnormalities; developmental delay; hypotonia; neurodegeneration; neurological disorder; respiratory complications.

Figure 1.. Schematic of reported TBCK variants.

(A) Diagram representing the location of reported variants within the genomic DNA for the canonical TBCK transcript. Black arrows correspond to the genomic loci for each of the reported variants. Color coding of the exons (rectangles) correspond to their contributing protein domain in panel B: exon 1 encodes the 5’UTR, dark purple exons (2–10) encode the protein kinase domain, light blue exons (15–22) encode the Rab-GAP TBC domain, and the orange exons (24–26) encode the rhodanese homology domain (RHOD). (B) Diagram of TBCK protein domains illustrating the reported variants and their frequencies. Each circle represents one individual with a homozygous mutation. For an individual with a compound heterozygous mutation, a distinct shape is given to match the two variants. Matching shapes correspond to the variants reported in the same individual. Some individuals with the same mutations are from the same family. Color coding of the domains corresponds to the color-coded exons in panel A. Mutation p. Arg126* is referred to as the founder mutation or the Boricua mutation associated with a patient population with severe phenotype [5]. The numbers under each domain denote the amino acid range for that domain, with the canonical protein consisting of 893 amino acids total in length. Abbreviations: 5’UTR, 5’ untranslated region; fs, frameshift; *, nonsense mutation; del, deletion; light gray letters, missense mutation.

Figure 2.. Symptoms and complications observed in individuals with TBCK syndrome.

An array of phenotypes are identified in 69 documented TBCK syndrome patients encompassing 23 ethnicities. Ratio and percentages of symptom frequency identified in the literature are reported. (Clockwise from top left) Neurologic phenotypes included areflexia (18 patients), reduced reflexes (19), hyperreflexia (1), seizures, and motor developmental delay (mild 18, moderate/severe 20). MRI commonly indicated abnormal white matter including hyperintensities and ventricular abnormalities. A lesser percent of patients (30.9%) had abnormal findings in the corpus collosum. Interrogation of the published literature indicates high variability in reporting of craniofacial anomalies. An open mouth phenotype including a tented upper lip and/or macroglossia (17.3%) was common, as was aberrant cranial form (microcephaly 3, macrocephaly 7, brachycephaly 5, turricephaly 3). Most patients had nonverbal speech delay. Cardiac abnormalities were reported in 12 patients. Eleven patients were reported to use G-tubes. Almost all patients reported hypotonia. Bone pathologies included delayed bone age, osteoporosis, and scoliosis reported in over half of the patients. Metabolic symptoms including high cholesterol, dyslipidemia, and hypertriglyceridemia were common. Respiratory maladies included ventilator dependency (13/30), tracheostomy (4/30), use of BiPAP (4/30), and apnea (2/30). Hearing impairment was relatively uncommon while vision impairment occurred in more than half of the patients. Vision-related phenotypes included ptosis (1), strabismus (12), impaired vision (20), nystagmus (8), and nocturnal lagophthalmos (1). All patients reported global developmental delay. The variability identified with these phenotypes and available data highlights the need for a more systematic diagnosis process. Abbreviation: MRI, magnetic resonance imaging.